Regio- and stereo-selective synthesis of trifluoromethylated isoxazolidines by 1,3-dipolar cycloaddition of 1,1,1-trifluoro-3-phenylsulfonylpropene with nitrones, and their conversion into trifluoromethylatedsyn-3-amino alcohols

摘要

J. CHEM. SOC. PERKIN TRANS, 1 1995 276 1 Regio- and stereo-selective synthesis of trifluoromethylated isoxazolidines by 1,3=digolar cycloaddition of 1,l,l-trifluoro-3-phenylsulfonylpropene with nitrones, and their conversion into trifluorornethy la ted syn-3-amino alcohols Hiroyasu Tsuge, Takashi Okano and Shoji Eguchi * Institute of Applied Organic Chemistry, Faculty of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoyu 464-01, Japan 1,1 ,1-Trifluoro-3-phenylsulfonylpropene1, a useful synthetic precursor for trifluoromethylated compounds, has been prepared from methyl phenyl sulfone 2 and ethyl trifluoroacetate. The 1,3-dipolar cycloaddition of 1 with various nitrones 5a-f gave 5-trifluoromethylisoxazolidines6a-f with a high degree of regio- and stereo- selectivity.The adducts 6a-f were converted into trifluoromethylated syn-3-amino alcohols 8a-d by desulfonylation with Na-Hg, followed by reductive cleavage of the N-0 bond by catalytic hydrogenation. Conversion of 8a and 8d into the cyclic carbamates 10a and 10d confirmed the assigned stereochemistry of 8 and, hence, of the cycloadduct 6a-f. Trifluoromethylated five-membered ring heterocycles are of current interest because of their potential biological activity. However, general methods for the regio- and stereo-selective synthesis of non-aromatic saturated heterocyclic compounds have yet to be established. Isoxazolidines, an important class of heterocycles, have potential as intermediates for nitrogen- and oxygen-containing compounds, such as 3-amino alcohols,2 compounds which are found in many glycosidic amino sugar^.^ 1,3-Dipolar cycloaddition of nitrones with olefins, an established preparative method for isoxa~olidines,~is capable of controlling a large number of stereochemical centres in one synthetic step because it usually proceeds by a concerted process.* Such reactions which occur with both electron- deficient and electron-rich olefins under mild conditions give the corresponding isoxazolidines both regio-and stereo-~electively.~However, there are few reported syntheses of trifluoromethylated isoxazolidines via 173-dipolar cycloaddition employing a trifluoromethylated electron-deficient olefin as a dip~larophile,~"*~even though the CF, group may activate the olefin by a strong inductive effect.1,1,I -'~rifluoro-3-phenylsulfonylpropene1 was earlier pre- pared from gaseous trifluoropropene by Taguchi et ~1.~and used as an electron-deficient dienophile with dienes to give 4 + 21 cycloadducts regio- and stereo-selectively. We report here both an alternative and convenient route to the olefin 1 from methyl phenyl sulfone 2 and ethyl trifluoroacetate, and the regio- and stereo-selective synthesis of trifluoromet hylated isoxazolidines by 1,3-dipoIar cycloaddition of 1 with some selected nitrones. We also describe the transformation of the cycloadducts to trifluoromethylated syn-3-amino alcohols. Results and discussion The olefin 1 was prepared as outlined in Scheme 1. Initially, the reaction of methyl phenyl sulfone 2 and ethyl trifluoroacetate in the presence of NaH gave trifluoromethylated sulfone 3, reduction of which with NaBH, afforded the alcohol 4.Dehydration of 4 was carried out by successive tosylation with toluene-p-sulfonyl chloride and elimination with triethylamine in CH,CI, at refluxing temperature. Since the elimination of the sulfonate was incomplete, DBU (1,8-diazabicyclo5.4.Oundec-7-ene) was added to complete the reaction. Work-up and 0 CH3S02Ph i, NaH/THF * Ls"2Ph ii, CF3C02Et CF: 2 3 CH2C12 1 4 Yield 38 from 2 Scheme 1 recrystallization gave the olefin 1 in 38 overall yield which is similar to that of Taguchi's route.6 The 1,3-dipolar cycloadditions of a variety of nitrones 5a--f with the olefin 1 in toluene were carried out at 1 10 "C for 12 h in a sealed tube to give the corresponding isoxazolidines 6a-f (Scheme 2, Table 1).The aromatic nitrones 5a--cprepared from R2 '* +/O-Toluene I 1+ PhOZS' CF3 5 6 3,4 -trans 4,s -trans Scheme 2 arenecarbaldehydes can be isolated by recrystallization and 5d was used after isolation by chromatography on a silica gel column. The unstable aliphatic nitrones 5e and 5f7 were generated in situ from N-methylhydroxylamine hydrochloride, triethylamine and paraformaldehyde or acetaldehyde, respec- tively at 110 "C in a sealed tube, and allowed to react with 1 for 12 h. The isoxazolidines 6a-d with aromatic substituents were obtained in almost quantitative yields.In contrast, 6e and 6f were obtained in moderate yields, together with some 2762 J. CHEM. soc. PERKIN TRANS. I 1995 Table 1 1,3-Dipolar cycloaddition of nitrones to olefin 1 Nitrones R' R2 Products Yield("/,) 5a Ph Me 6a 95 5b 5c p-MeOC,H, Ph Me Bu 6b 6c 99 95 5d Ph Ph 6d 99 5e H Me 6e 65 5f Me Me 6f 39 Table 2 The vicinal coupling constants (J3,4, J4,J in 6a-f R2 I 6a 8.4 4.0 6b 8.4 4.0 8.2 3.8 6d 7.2 3.8PhOZS CF, a6e -4.9 6 6f 8.2 4.0 a The vicinal coupling constant (J3,4)of 6e(R' = H, R2 = CH3) could not be determined by the 'H NMR spectrum analysis. unidentified low-yield products. The unstable nature of the aliphatic nitrones 5e and 5f seems to retard the cycloaddition toward 1 compared with 5a-d.The 'H NMR spectra of the adducts 6a-f revealed that they were almost single products, indicating that the cycloaddition process proceeded with high regio-( 98) and stereo-selectivity. The existence of doublet quartet signals confirmed the 5-trifluoromethylisoxazolidine structure (for 5-H 6, 3.1-5.0; J4,53.8-4.0 and J4-H,F6.7-8.2 Hz). The stereochemistry of the adducts 6a-f was assigned as 3,4-transand 4,5-trcms,since the vicinal coupling constants (J3,4 and J4,5in Table 2) were similar to the reported ones (J3,46.5 and J4,53.0 Hz) of 5-methyl-2,3-diphenyl-4-phenylsulfonyl-isoxazolidine.8 The rigorous elucidation of the stereochemistry was performed by the chemical conversion of the compounds into six-membered ring carbamates, vide infru.As mentioned above, isoxazolidines can be considered as precursors for functionalized acyclic compounds and accord- ingly, compounds 6a4 were transformed into the correspond- ing trifluoromethylated syn-3-amino alcohols 8a-d as shown in Scheme 3. Reductive desulfonylation of the isoxazolidines 6a-d was carried out with 5 Na-Hg9 in THF-CH,OH at room temperature,? followed by catalytic hydrogenation with 10 Pd-C lo to give, via N-0 bond cleavage, the 3-amino alcohols 8a-d in 17-26 overall yields (Table 3) with no epimerization at positions C-3 and C-5. This was established by analysis of the 'H NMR spectra of the reaction mixtures of 7a4 which showed the presence of a single stereoisomer in each case.The aliphatic 3-amino alcohols amp; and 8f could not be isolated, probably because they were lost during work-up as a result of their volatility and hydrophilicity. As described above, the stereochemistry of 6a-d was determined from the vicinal coupling constants (J3,4and J4,J of the 'H NMR spectra. In general, however, there is some equivocality in the stereochemical determination of isoxazo- lidine by the 'H NMR coupling constants because of the t After typical work-up, the resulting compound was homogeneous by TLC on silica gel and was used directly for N-0 bond cleavage by catalytic hydrogenation. In the case of desulfonylation of 6a, however, the intermediate 7a was isolated by silica gel column chromatography with hexane-CH2C1, (2 : 1) as the eluent to confirm the shown structure (see Experimental section).Table 3 Transformation of 6a-d to Sad Yield () 6 R' R2 Products of 8from 6 6a Ph Me 8a 25 6c 6b Ph p-MeOC,H, Bu Me 8c 8b 17 21 6d Ph Ph 8d 26 Table 4 'H NMR coupling constants of 10a, d (in Hz) Jab= 14.2,Jbd = 5.7 Jab= 14.0,Jbc = 3.1 Jac = 12.1, Jbc = 2.2 Jac Jad 2 11.2 Jad = 11.5 Jbd= 5.7 Hz, 10 Pd-C MeOHI 8a-d 1,3 -syn Scheme 3 flexibility of the five-membered isoxazolidine ring structure. For example, the vicinal coupling constants (J3,4and J4,Jof 6d are slightly different from those of 6a-q 6eand 6f as shown in Table 2. In order to confirm the assigned stereochemistry of 6a-f, we converted the 1,3-amino alcohols 8a and 8d into the cyclic carbamates 10a and 10bby reaction with diimidazol-1-yl ketone 9 in 93 and 29 yield, respectively.l2 As shown in Table 4, large coupling constants, J,, 12.1 Hz, Jad11.5 Hz for 10a, Jac = Jad1 1.2 Hz for 1Odrevealed the axial- axial alignment of Haand H,. This means that the relative stereochemistry of the trifluoromethyl group and the phenyl group is syn. The E configuration of the olefin 1 would have been retained since the 1,3-dipolar cycloaddition of nitrones is known to proceed in a concerted manner13 and the cycloaddition of nitrones 5a-f to 1 proceeded with high J. CHEM. SOC. PERKIN TRANS. I 1995 stereoselectivity. In the light of these results, the isoxazolidines 6a-f were confirmed to be all trans isomers.Although aldonitrones are known generally to exist in the most stable 2c~nfiguration,~some C-phenylnitrones have been converted into the Eisomer in competition with cycloaddition. For example, N-methyl-C-phenylnitrone5a exists as a mixture of 2 and E isomers at 147 OC.15 The AG* values for the interconversion of configurations (Z -5) at 147 "C were reported as 33.1 kcal mol-l (E-2)and 34.6 kcal mol-' (2-E), respectively.' The energies required for such interconversion are slightly larger than the AG" value of the cycloaddition of N-methyl-C-phenylnitrone 5a with ethyl crotonate (25.4 kcal mol-' at 85 OC).I6 On the other hand, 1,3- dipolar cycloadditions occur by an endo or exo transition state as for Diels-Alder reactions.Four kinds of transition state can be considered for the 1,3-dipolar cycloaddition of 5a with olefins as shown in Scheme 4. When an electron-withdrawing 4 -*,X CF3lcF3*x II 3,4 -cis X E-endo 43 -transI Z-ex0 X =COZMe, NO2 3,4 -trans 43 -transX E -ex0 Z-endo,=,,,,I Scheme 4 group is present in the dipolarophile, an endo transition state would be favourable because of the secondary orbital interaction between a p-orbital of the nitrogen atom and a 71-orbital such as found in the GO of the electron-withdrawing group. 'Bravo reported that the 1,3-dipolar cycloaddition of N-methyl-C-phenylnitrone 5a with 4,4,4-trifluorocrotonate furnished the corresponding 3,4-cis and 4,5-trans-isoxazolid- ine.'" Tanaka also reported that the 1,3-dipolar cycloaddition of 5a with 3,3,3-trifluoro-l -nitroprop-l-ene afforded the corresponding 3,4-cis-4,5-tr~ns-isoxazolidine.~~Both authors invoked the initial conversion of the nitrone 5a from the 2into the E form before the cycloaddition step and attributed the stereochemistry for the 3,4-cis-4,5-trans-isoxazolidinesto the attractive x-71 orbital overlap between the electron-withdrawing group (ie.,X = C0,Me and NO,) and the phenyl group on the carbon atom of nitrone 5a and the resulting E-endo transition state. Based on the observed stereochemistry of the adducts 6a-f, the stereochemistry of the transition state of the present 1,3- dipolar cycloaddition should be E-exo or Z-endo.Although benzoic acid has been reported to catalyse the Z-+E isomerization of nitrones, ' it had no effect on the 1,3-dipolar cycloaddition of 1 with 5a.S Thus, Z --+E isomerization is not necessary for the reaction of 1 with nitrones even though $ The reactions of 1 and an equimolar amount of 5a were conducted at 80 "C for 30 min in sealed tubes in the presence of 0, 1 and 10benzoic acid, respectively.The conversions of 1 to 6a were found to be 79, 75 and 79, respectively by 'HNMR spectra. isomerization of the nitrone must be competitive with cycloaddition. In the reaction of 1with nitrones, a repulsive van der Waals steric interaction between the sulfonyl group and the substituent on the nitrone carbon plays an important role in determining the stereochemistry of the isoxazolidine.Consequently, the cycloaddition of 1with nitrones proceeds via a Z-endo transition state, which minimizes the steric interaction, to give all trans isoxazolidines. Croce et al. reported the 1,3-dipolar cycloaddition of C,N-diphenylnitrone to 1 -phenylsulfonylprop- 1-ene.' In that case, the regio- and stereo-selectivities were identical with those described here. This result suggests that the trifluoromethyl group does not determine the regio- and stereo-selectivity of the cycloaddition of the nitrone. In order to examine the effect of the CF, group on the cycloaddition, a mixture of N-methyl-C-phenylnitrone 5a (0.6 mmol) with 1 (0.3 mmol) and 1-phenylsulfonylprop-1 -ene (0.3 mmol) was heated in benzene (3 cm3) at 80 "C for 45 min in a sealed tube.Analysis of the 'H NMR spectrum indicated that the cycloaddition of 1 occurred with 70 conversion, while 1-phenylsulfonylprop-1-ene was unchanged. This result demonstrates that the presence of a CF, group in the dipolarophile 1 for the cydoaddition of nitrones makes the olefin more reactive mainly by lowering the energy level of the LUMO. Experimental Melting points were taken on a Yanagimoto micro-melting point apparatus and are uncorrected. IR spectra were measured on a JASCO FT/IR 5300 spectrometer. 'H and I3C NMR spectra were measured on a Varian GEMINI 200 spectrometer at 200 and at 50 MHz, respectively, for samples in CDC1, solution with Me4Si as an internal standard. '9F NMR spectra were measured on a Hitachi FT-NMR R-90F spectrometer at 85 MHz for samples in CDCl, solutions with CFCl, as an internal standard.J Values are given in Hz. Microanalyses were performed on a Perkin-Elmer 2400s elemental analyser. Chromatography was performed on silica gel columns (Fuji- Davison BW-300). Thin layer chromatography was performed on Merck Kieselgel 60 F254. Mass spectra (EI) were obtained using a JEOL JMS-AX 505 HA mass spectrometer at 70 eV. 1,1,l-Trifluoro-3-phenylsulfonylpropene1 To a stirred THF (20 cm3) solution of methyl phenyl sulfone 2 (1.60 g, 10 mmol) under N, at 0 "C was added NaH (60 oil dispersion; 600 mg, 15 mmol) in portions after which the resulting suspension was stirred at 0 "C for 10 min, and then treated dropwise with ethyl trifluoroacetate (3.60 cm3, 30 mmol) at 0 "C.After 2h under reflux, the resulting solution was poured into saturated aq. NaCl (250 cm3) and extracted with Et20 (100 cm3 x 4). The combined extracts were dried (MgSO,) and evaporated under reduced pressure to give 3(1.80 g, v,,, 3414, 1732 crr-'). Without purification, NaBH, (2.50 g, 10 mmol) was added to a solution of 3 (1.80 g) in MeOH (20 cm3). After being stirred overnight at room temperature, the solution was poured into saturated aq. NaCl (200 cm3) and extracted with Et20 (100 cm3 x 4). The combined extracts were dried (MgSO,) and evaporated under reduced pressure. The residue was recrystallized from Et,O-hexane to give 4 (1.40 g, 57 from sulfone 2), mp 73-74 "C (Found: C, 42.6; H, 3.3. C,H9F,03S requires C,42.52; H, 3.57); v,,,(KBr)/cm-' 3447, 1265 and 1127;6,7.59-8.01 (5 H, m), 4.61 (1 H, dqd, J 10.1,6.4 and 3.8), 3.67-3.82 (1 H, m) and 3.44 (2 H, m); 8, 139.1, 135.1, 130.1, 128.4, 123.9 (4, J280), 66.2 (9, J33) and 56.3;6, -79.9 (s); m/z (EI) 254 (M', lo), 141 (65) and 77 (100).To a stirred solution of 4 (1.40 g, 5.7 mmol) and Et3N (1.60 cm', 11 mmol) in CH,Cl, (20 cm3) was added solid toluene-p- sulfonyl chloride (1.08 g, 5.7 mmol) in portions. After 2 h under reflux the mixture was treated with DBU (868 mg, 5.7 mmol) and heated under reflux for a further 1 h. The solution was then poured into saturated aq. NaHCO, (200 cm3) and extracted with CH2C12 (100 cm3 x 4). The combined extracts were washed with aq.HCl (1 mol dmp3; 100 cm3 x 2), dried (MgSO,), and evaporated under reduced pressure. The residue was recrystallized from Et,O-hexane to give 1 as a colourless solid (890 mg, 67; 38 from sulfone 2), mp 68-69 "C. The sulfone 1 was identified by comparison of its 'H NMR spectrum with that reported in the literature.6 N-Methyl-C-phenylnitrone 5a (mp 80-81 "C; lit., l9 81-82 "C), C-(4-methoxyphenyl)-N-methylnitrone 5b (mp 84-86 "C; lit.,,' 85-87 "C) and C,N-diphenylnitrone 5d (mp 110- 11 1 "C; lit.,,' 112-1 14 "C) were prepared according to literature methods. N-Butyl- C-phen ylnitrone 5c Following a literature method,22 several small cuttings of sodium (1.40 g, 60 mmol) were added to a stirred solution of benzaldehyde oxime (7.20 g, 60 mmol) in dry MeOH (50 cm3) and stirring continued for 10 min.1-Iodobutane (6.90 cm3, 61 mmol) was added to the resulting solution which, after being stirred overnight, was evaporated under reduced pressure. The residue was dissolved in Et20 (30 cm3) and after removal of NaI by filtration, was evaporated under reduced pressure. The residue was chromatographed on a silica gel column with hexane-EtOAc (2 :1) as the eluent to give 5c (620 mg, 6) as a colourless oil (eluent: AcOEt-hexane, 2: 1, R, 0.34) (Found: M+, 177.1 154. C1 'HISNO requires M, 177.1 154); v,,,(neat)/ cm-' 1582, 1458 and 1157; SH 8.20-8.27 (6 H, m), 3.94 (2 H, t, J7.0), 2.00 (2 H, tt, J9.8 and 7.0), 1.43 (2 H, tq, J9.8 and 7.4) and 0.98 (3 H, t, J7.3);6, 134.5, 130.9, 130.6, 128.8 (2 C), 67.3,29.8,19.8 and 13.6; m/z (EI) 177 (M+,5973, I18 (100) and 91 (46).General procedure for 1,3-dipolar cycloaddition of nitrones 5a-d with 1 A solution of 1 in toluene and an equimolar amount of the appropriate nitrone 5a-d was heated at 110 "C under argon in a sealed tube for 12 h, after which the mixture was evaporated under reduced pressure and the residue chromatographed on a silica gel column (elution: CH,Cl,). (3R* ,4R* ,5S*)-2-Methyl-3-phenyl4phenylsulfonyl-5-tri-fluorornethylisoxazolidine 6a. Compound 6a was obtained as above from 1 (708 mg, 3.00 mmol), 5a (405 mg, 3.00 mmol) and toluene (2 cm3) as a colourless solid (1.06 g, 9573, mp 128- 129deg;C (Found: C, 54.7; H, 4.3; N, 3.7. C,,H16F,N0,S requires C, 54.95; H, 4.34; N, 3.78); v,,,(KBr)/cmpl 1316, 1283 and 1175;dH7.25-7.19 (10 H, m), 4.83 (1 H, qd, J7.2 and 4.0),4.23(1H,dd,J8.4and4.0),3.97(1H,d,J8.4)and2.61(3 H, s); 6, 137.7, 134.9, 134.8, 129.8, 129.4, 129.2, 128.9, 128.5, 123.8 (9, J 284), 75.1, 75.0 (9, J 34), 74.4 and 42.8; BF -78.9 (d, J7); m/z (EI) 371 (M', 18), 229 (36) and 160 (100).(3R*,4R*,5S*)-3-(4-Methoxyphenyl)-2-rnethyl4phenylsulf-onyl-5-trifluoromethylisoxazolidine 6b. Compound 6b was ob- tained as above from 1 (236 mg, 1.00 mmol), 5b (165 mg, 1.00 mmol) and toluene (3 cm3) as a colourless solid (399 mg, 9973, mp 145-147 "C (Found: C, 53.7; H, 4.5; N, 3.5. Cl,Hl,F3N04S requires C, 53.86; H, 4.52; N, 3.49); v,,,(KBr)/cm-' 1254, 1177 and 1132; SH 7.80-7.42 (5 H, m), 7.12 (2 H, d, J 8.9), 6.76 (2 H, d, J 8.9), 4.80 (1 H, qd, J 7.2 and 4.0),4.17(1 H,dd, J8.4and4.0),3.94(1 H,d,J8.4),3.78(3H, s) and 2.59 (3 H, s); 6, 160.5, 137.8, 134.9, 129.8, 129.7, 128.9, 126.6, 123.8 (4,J284), 114.6, 75.0, 74.9 (9, J34), 73.9, 55.5 and 42.7; 6, -76.0 (d, J 3); m/z (EI) 401 (M', 27), 259 (25) and 190 (100).(3R*,4R*,5S*)-2-Butyl-3-phenyl-4-phenylsulfonyl-5-trifluoro-methylisoxazolidine 6c. Compound 6c was obtained as above J. CHEM. SOC. PERKIN TRANS. 1 1995 from 1 (260 mg, 1.10 mmol), 5c (195 mg, 1.10 mmol) and toluene (4 cm3) as a colourless solid (433 mg, 9573, mp 66- 67 "C (Found: C, 58.35; H, 5.1; N, 3.35. C2,H2,F3N03S requires C, 58.10; H, 5.36; N, 3.39); v,,,(KBr)/cmpl 1329, 1281 and 1155; 6, 7.79-7.19 (10 H, m), 4.80 (1 H, qd, J 7.2 and 3.8), 4.60 (1 H, d, J 8.2), 4.18 (1 H, dd, J 8.2 and 3.8), 2.77-2.51 (2 H, m), 1.65-1.10 (4 H, m) and 0.78 (3 H, t, J 7.2); Sc 137.8, 135.5, 134.9, 129.8, 129.1 (2 C), 128.9, 128.8, 128.5, 123.8 (4,J 285), 75.1, 74.9 (q, J 34), 72.5, 55.6, 29.6, and 20.1; aF -76.0 (d, J 7); m/z (EI) 413 (M+, 57), 370 (57) and 202 (100).(3R*,4R*,5S*)-2,3-Diphenyl-4-phenylsulfonyl-5-trifluoro-rnethylisoxazolidine 6d. Compound 6d was obtained as above from 1 (708 mg, 3.00 mmol), 5d (592 mg, 3 mmol) and toluene (18 cm3) as a colourless solid (1.30 g, 9973, mp 112-1 13 "C (Found: C, 60.7; H, 4.0; N, 3.0. C,,Hl,F,N03S requires C, 60.96; H, 4.19; N, 3.23); v,,,(KBr)/cm-' 1271, 1186 and 1157; dH7.85-6.95 (15 H, m), 4.99 (1 H, qd, J 7.2 and 3.8), 4.79 (1 H, d,J7.2)and4.33(1 H,dd,J7.2and3.8);dC147.6,137.5, 136.3, 135.1, 134.9, 130.0, 129.3, 129.1, 129.0, 128.2, 125.8, 123.6(q7J 284), 119.7,75.9,75.1 (9, J34)and71.8;dF -75.6(d, J5);mlz (EI) 433 (M', loo), 222 (100) and 77 (48).(4R*,5S*)-2-Methyl-4-phenylsulfonyl-5-trifluoromethy~isoxa-zolidine 6e. To a solution of 1 (98 mg, 0.40 mmol) in toluene (3 cm3) in a glass tube under argon was added N-methylhydroxyl- amine hydrochloride (40 mg, 0.50 mmol), triethylamine (46 mg, 0.45 mmol) and paraformaldehyde (30 mg, 1.00 mmol). After the mixture had been treated at 110 "C for 12 h, it was evaporated under reduced pressure, and the residue was chromatographed on a silica gel column with hexane-CH,Cl, (3 :1) as the eluent to give a colourless solid (80 mg, 65), mp 120-121 "C (Found: C, 44.9; H, 4.2; N, 4.6.CllHl,F,NO,S requires C, 44.74; H, 4.10; N, 4.74); v,,,(KBr)/cm-' 1312, 1277 and 1154; BH 7.98-7.59 (5 H, m), 4.69 (1 H, qd, J 6.7 and 4.9),4.38-4.12(1H,m),3.56(1H,brs),3.04(1H,brs)and2.80 (3 H, s);6, 137.8, 135.2, 130.2, 129.0, 123.5 (4, J278), 75.4(q, J 33), 68.5, 58.2 and 45.2; SF -76.7 (d, J 5); m/z (ET) 295 (M+, 1 I ), 153 (43), 84 (1 00) and 77 (2 1). (3R*,4R*,5S*)-2,3-Dimethyl4phenylsulfonyl-5-trifluoro-rnethylisoxazolidine 6f. Compound 6f was obtained similarly from 1 (944 mg, 4.00 mmol), N-methylhydroxylamine hydrochloride (367 mg, 4.40 mmol), Et3N (445 mg, 4.40 mmol), acetaldehyde (441 mg, 10.0 mmol) and toluene (18 cm3) as a colourless solid (391 mg, 32), mp 119-121 "C (Found: C, 46.6; H, 4.6; N, 4.4.C12H14F,N03S requires C, 46.60; H, 4.56; N, 4.53); vmax(KBr)/cm-' 1277, 1152 and 1132;6,7.97-7.59 (5 H, m), 4.57 (1 H, qd, J 7.2 and 4.0), 3.74 (1 H, dd, J 8.2 and 4.0), 3.14 (qd, 1 H, J8.2 and 7.0), 2.73 (3 H, s) and 1.21 (3 H, d, J6.2); 6, 137.8, 135.2, 130.15, 129.1, 123.6 (9, J 284), 74.6 (q, J 34), 74.1, 65.2, 43.1 and 16.5; 6, -76.6 (d, J 5);m/z (EI) 309 (M', 5579, 167 (100) and 153 (30). General procedure for the preparation of 3-amino alcohols 8a-d To a solution of the isoxazolidine 6a4 in MeOH was added portionwise 5 sodium amalgam (8 equiv. of Na) and Na,HPO, (8 equiv.) under N,. After being stirred for 2 days at room temperature, the mixture was freed of deposited Hg metal by decantation and then evaporated under reduced pressure.10 Aq. NaOH was added to the residue and the resulting mixture was extracted with Et,O. The combined extracts were dried (MgSO,) and evaporated under reduced pressure to give the desulfonylated compounds 7. Without purification, 7 was dissolved in MeOH and 10 palladium-on-carbon was added to the solution. The mixture was stirred under an atmospheric pressure of H, for 3 days at room temperature, after which the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was chromatographed on a silica gel column (elution :AcOEt). J. CHEM. SOC. PERKIN TRANS. 1 1995 (2R*,4R*)-1,1 ,l-Trifluoro-4-methylamino-4-phenylbutan-2-01 8a.Compound 8a was obtained as above from 6a (928 mg, 2.50 mmol), 5 Na-Hg (9.20 g, 20.0 mmol of Na), Na,HPO, (2.98 g, 21 .O mmol), 10 Pd-C (80 mg, 0.08 mmol) and a mixture of dry THF (3 cm3) and dry MeOH (1 5 cm3) as a yellow solid (148 mg, 25), mp 101-102deg;C (Found: C, 56.6; H, 6.1; N, 6.0. CllH14F3N0 requires C, 56.65; H, 6.05; N, 6.01); v,,,(KBr)/cm-' 3281, 1167 and 1127; dH 7.45-7.20 (5 H, m), 4.30 (I H, dqd, J 10.3, 6.5 and 3.7), 4.18-3.79 (2 H, In), 3.72-3.65 (1 H, m), 2.27 (3 H, s) and 2.07-1.86 (2 H, m); dc 141.7, 129.4, 128.4, 126.6, 125.0 (9, J280), 71.5 (9, J31), 64.2,34.6 (4, J 1.9) and 33.2; 6, -81.4 (d, J5); m/z (EI) 233 (M', 3), 121 (64) and 120 (100). (3R* ,5S*)-2-Methyl-3-phenyl-5-trifluoromethylisoxazo~dine 7a. Compound 7a was obtained as above from 6a (200 mg, 0.540 mmol), 5 Na-Hg (1.01 g, 2.20 mmol of Na) and Na,HPO, (350 mg, 2.50 mmol) as a yellow oil (39 mg, 31) (eluent :hexane-CH,Cl,, 2 : 1, R, 0.25) (Found: M ', 231.0872.C, ,H,,F,NO requires M, 231.0871); v,,,(neat)/cm-' 1279, 1165 and 1125; 6, 7.40-7.33 (5 H, m), 4.46 (1 H, dqd, J 8.8, 7.2 and 6.3), 3.56 (I H, dd, J 10.2 and 7.2), 2.87 (1 H, ddd, J 13.0, 8.8 and 7.2), 2.60 (3 H, s) and 2.52 (I H, ddd, J 13.0, 10.2 and 6.3);6,137.4, 129.3, 128.9, 128.1, 125.1 (9, J282),73.8(q, J33), 73.4,43.2 and 40.0; dF -78.0 (d, J7); m/z (EI) 231 (M', loo), 154 (54) and I34 (50). (2R*,4R*)-l,1,l-Trifluoro-4-(4-methoxyphenyl)4(methyl-amino)butan-2-01 8b. Compound 8b was obtained as above from 6b (I .04 g, 2.60 mmol), 5 Na-Hg (9.20 g, 20.0 mmol of Na), Na,HPO, (2.98 g, 21.0 mmol), 10 Pd-C (80 mg, 0.08 mmol) and a mixture of dry THF (5 cm3) and dry MeOH (15 cm3) as a colourless solid (145 mg, 21), mp 108-109deg;C; (Found: C, 54.8; H, 6.1; N, 5.3.C,,H,,F,NO, requires C, 54.75; H, 6.13; N, 5.32); v,,,(KBr)/cm-' 3281, 1250 and 1123 cm I; 8, 7.42 (2 H, d, J 8.8), 6.92 (2 H, d, J8.8), 4.29 (I H, dqd, J 10.3,6.6 and 3.7), 3.82 (3 H, s), 3.66-3.59 (1 H, m), 2.25 (3 H, s) and 2.05-1.83 (2 H, m)$;dc 159.7, 133.9, 127.7, 125.1 (9, J280), 114.6,71.4(q, J31),63.5,55.5,34.6(q, J1.8)and33.1;dF --81.4 (s); mi. (EI) 263 (M', 3), 151 (35) and 150 (100). (2R*,4R*)-4-Butylamino-l,1,1-t-rifluoro-4-phenylbutan-2-01 amp;. Compound 8c was obtained as above from 6c (1.03 g, 2.60 mmol), 5 Na-Hg (9.20 g, 20.0 mmol of Na), Na,HPO, (2.98 g, 21 .O mmol), 10 Pd-C (80 mg, 0.08 mmol) and a mixture of dry THF (5 cm3) and dry MeOH (15 cm3) as a colourless solid (I 18 mg, 17), mp 93-94 "C (Found: C, 61.2; H, 7.3; N, 5.0.Cl,H2,F,N0 requires C, 61.08; H, 7.32; N, 5.09); v,,,(KBr)icm 3268, 1275 and 1163; 6, 7.44-7.19 (5 H, m), 4.33 (I H, dqd, J 10.4, 6.6 and 4.0), 3.81-3.74 (1 H, m), 2.06- 1.85(2H,m),2.57-2.34(2H,m), 1.49-1.20(4H,m)andO.E;5(3 H, t, J6.6);46, 142.3, 129.4, 128.3, 126.4, 125.0(q, J280), 71.6 (4, J 31), 62.7, 46.5, 34.8, 32.0, 20.3 and 13.9; amp; -81.4 (s); m/z (EI) 275 (M', 2), 203 (87) and 162 (100). (2R* ,4R*)-4-Anilino-l, 1,l -trifluor0-4-phenylbutan-2-01 8d. Compound 8d was obtained as above from 6d (300 mg, 0.680 mmol), 5 Na--Hg (2.60 g, 6.00 mmol of Na), Na,HP04 (850 mg, 6.00 mmol), 10 Pd-C (30 mg, 0.02 mmol) and a mixture of dry THF (3 cm3) and dry MeOH (10 cm3) as an orange- coloured solid (50 mg, 26), mp 90-92 "C (Found: C, 65.2; H, 5.6; N, 4.5.C,6H,6F3N0 requires C, 65.08; H, 5.46; N, 4.74); vmax(KBr)/cm' 3409, 1277 and 1132; BH 7.35-6.61 (10 H, m), 4.62 ( 1 H, dd, J 8.5 and 6.5), 4.07 ( 1 H, dqd, J 10.5,7.0 and 2.5), 4.04-3.52(2H,m),2.19(1 H,ddd, J14.5,6.5and2.5)and2.09 (1 H, ddd, J 14.5, 10.5 and 8.5); dc 146.8, 142.5, 129.6, 129.4, 128.2, 126.6, 125.1 (q, J281), 119.3, 115.1, 70.0 (q, J31), 57.2 and 37.0; 6, -80.8 (d, J 7); rn/z (EI) 295 (Mi, 9373, 186 (36) and 182 (100). 4 NH and OH signals are missing due to signal broadening.(4R*,6R*)-3-Methyl-4-phenyl-6-trifluoromethyl-1,3-oxazinan-2-one 10a To a refluxing solution of 8a (155 mg, 0.66 mmol) in dry CH3CN (5 cm3) was added a solution of diimidazol-1-yl ketone 9 (120 mg, 1.35 mmol) in CH3CN (5 cm3) under N,. After 5 h under reflux the mixture was evaporated under reduced pressure, and the residue was chromatographed on a silica gel column with hexane-EtOAc (1 : 1) as the eluent to give 10a as a colourless solid (159 mg, 930/,), mp 130-131 "C(Found: C, 55.6; H, 4.7; N, 5.4. C,,H,,F,NO, requires C, 55.60; H, 4.67; N, 5.40) v,,,(KBr)/cm-' 1692, 1144 and 11 19;dH7.48-7.24 (5 H, m),4.69(1 H,dqd, J12.0,7.8and2.2),4.54(1 H,dd, J11.4and 5.5),2.74(3H,s),2.49(1 H,ddd, J14.2,5.5and2.2)and2.17(1 H, ddd, J 14.2, 12.2 and 11.6); S, 152.7, 139.0, 129.8, 129.4, 127.0, 122.6 (4, J 279), 72.4 (4, J 34), 60.7, 34.6 and 31.7; 6, -79.5 (s); m/z (EI) 279 (M', loo), 182 (30) and 118 (54).(4R*,6R*)-3,4-Diphenyl-6-trifluoromethyl-1,3-oxazinan-2-one 10d Compound 1Od was obtained similarly from 8d (57 mg, 0.18 mmol) in dry CH3CN (5 cm3) and diimidazol-I-yl ketone 9 (58 mg, 0.36 mmol) in dry CH,CN (3 cm3) solution as a colourless solid (34 mg, 29), mp 143-145 "C (Found: C, 63.4; H, 4.1; N, 4.35. C,,H,,F,N02 requires C, 63.55; H, 4.39; N, 4.36); v,,,(KBr)/cm-' 1692, 1402 and 1177; 6, 7.28-7.04 (10 H, m), 5.05 (1 H, dd, J 14.0 and 11.2), 4.91 (1 H, dqd, J 11.3, 5.6 and 3.1),2.59(1 H,ddd, J14.0,5.7and3.l)and2.46(1H,dt, J14.0 and 11.2); 6, 151.5, 139.8, 138.4, 129.2, 129.0, 128.2, 128.0, 127.8, 127.6, 122.7 (9, J 279), 73.0 (4, J 35), 61.9 and 31.1; dF -79.4(d, J5);rn/z(EI) 321 (M+,91), 185(100)and 165 (43).References 1 (a)For a review on fluorine-containing heterocyclic compounds, see: K. Tanaka, J. Synth. Org. Chem., Jpn. 1980, 48, 16 and references cited therein; (b) For a recent review on trifluoromethylation, see: M. A. McClinton and D. A. McClinton, Tetrahedron, 1992, 48, 6555; (c) For a review on fluorinated heterocycles, see: E. Differding, W. Frick, R. W. Lang, P. Martin, C. Schmit, S. Veenstra and H. Greuter, Bull. Soc. Chim. Belg., 1990, 99, 647; (d) For biomed-ical aspects, see: J. T. Welch and S. 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Umezawa, Chem. Pharm. Bull., 1962,10,492. Received 5th June 1995 20 0.H. Wheeler and P. H. Groce, J. Am. Chem. Soc., 1956,78,3363. Accepted 6th July 1995